Suchergebnisse

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers. ; Work in MPC lab is supported by Liverpool University, Newcastle University and a Wellcome Institutional Support Fund Award. Work done in A.G.'s lab was supported by Bulgarian National Science Fund grant # DN11/17. Work in the PP lab is supported by grants from the Agence Nationale pour la Recherche (ANR), the Ligue Contre le Cancer (équipe labellisée), SIRIC Montpellier Cancer (INCa Inserm DGOS 12553) and the MSDAvenir fund. ULM was funded by the Royal Society RG170342. IHL was funded from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 754510. Work in the DR lab is supported by a Wellcome Trust Seed Award in Science (206103/Z/17/Z). Work of JMGH was funded by a Wellcome Trust Investigator Award [106951/Z/15/Z] and a Royal Society Wolfson Research Merit Award